The Government has rights in this invention pursuant to Contract No. DE-AC03-76SF-00098 awarded by the U.S. Department of Energy.
Siderophores are highly selective ferric chelating agents synthesized and released by microorganisms to ensure the presence of sufficient iron for survival, in readily usable, i.e. solubilized, form. The preparation of synthetic analogs of siderophores is of some interest, as such analogs could have important potential applications as clinical iron removal agents, particularly for patients who suffer from blood diseases such as betathalassemia, the treatment of which requires the regular transfusion of whole blood and results in the accumulation of massive tissue iron deposits. Because of the similarity in coordination properties between the ferric ion and the tetravalent actinides, synthetic analogs of siderophores are also potential chelators of tetravalent actinides, which present significant biological hazards associated with nuclear technology. Normally, such actinide chelating agents will be octadentate ligands, as opposed to the generally hexadentate siderophores. Other uses, such as radionuclide chelation in nuclear medicine applications, for example, are also clearly possible.
The metal-binding ligands of siderophores are usually either catechols (dihydrobenzene analogues; Formula 1) or hydroxamic acids (Formula 2). ##STR1##
The siderophore enterobactin, for example, incorporates three catechol groups as a hexadentate ligand. Synthetic analogs of catechol-based siderophores are also known. See, e.g., U.S. Pat. No. 4,530,963 to DeVoe et al., issued July 23, 1985. However, the weak acidity of catechol and the required loss of two protons per catechol group at or about neutral pH limit the effectiveness of catechol-based ligands. It is therefore desirable to provide a medicinally useful chelating agent having a lower pK.sub.a that is more versatile than catechol-based compounds. Uninegative ligands, i.e., ligands having a single negative charge at neutral pH, are particularly desirable, in contrast to the corresponding highly charged ferric and plutonium catechol complexes. The importance of both pK.sub.a and a monoprotic acid ligand is illustrated by the exponential nature of the proton-dependent metal-ligand complex formation constant (Eq. 1). ##STR2##
Derivatives of 1-hydroxy-2-pyridinone (Formula 3; "HOPO") are of particular interest, since the ligand and its mono-anion (Formula 4) have a zwitterionic resonance form (Formula 5) that is isoelectronic with the catechol dianion. The abbreviation "HOPO" will hereinafter be used to include 1-hydroxy-2-pyridinone analogues as well as isomers of tautomers thereof, in either protonated or deprotonated form.
The HOPO structure possesses some important synthetic advantages. The 6-carboxylic acid structure (Formula 6) can be made in a straightforward manner, and further, the placement of functional groups at the 1, 2, and 6 positions makes possible the activation of the carboxylic acid moiety without the need for a protecting group at the N-hydroxyl position. HOPO derivatives provided by the present invention also have the desired low pK.sub.a and are uninegative at neutral pH. ##STR3##